More than 1.1 million men are diagnosed with prostate cancer globally and causing 300,000 cancer-specific deaths each year. The impact is particularly profound for African-American men who suffer significantly increased mortality rates. The sources of these substantial prostate cancer disparities are unclear. Our application focuses on disruption of circadian rhythms and prostate cancer risk in a racially/ethnically diverse cohort. The rationale is based on the classification of nightshift work as a probable human carcinogen by the International Agency for Research on Cancer, with a proposed mechanism through circadian disruption. Our preliminary data from cohorts of white men show that several key components of circadian disruption, including low melatonin, increased sleep disruption, and variation in circadian genes, all are linked with with higher risk of advanced prostate cancer. African-American men have altered circadian rhythms and low melatonin compared to men of other races. We propose an integrative molecular epidemiology study of circadian disruption to investigate the association between circadian disruption and prostate cancer risk, and the extent to which circadian disruption explains racial disparities. The study will be nested among men in the prospective Multiethnic Cohort (MEC), ongoing since 1993 and including Latino, African-American, Hawaiian, Japanese and white men. We will measure pre-diagnostic urinary 6-sulfatoxymelatonin, the primary metabolite of melatonin, among 1,648 prostate cancer cases (N=801 with advanced/fatal disease) diagnosed 2000 to 2014 and 3,296 matched controls. We will use pre- existing data from genome-wide association studies to investigate genetic variants in circadian genes and known prostate cancer risk loci with 6-sulfatoxymelatonin levels. Because obesity impairs circadian rhythm, we will use anthropometric data to explore the extent to which the link between obesity and prostate cancer is driven through altered circadian rhythm. For all analyses, a primary goal is to formally compare and contrast the associations by race/ethnicity. The hypothesis that disruption of circadian rhythms is a risk factor for prostate cancer is promising, but has been addressed somewhat superficially; there are only sparse data from the few studies of advanced disease and no study has been conducted within a racially/ethnically diverse population. However, the careful investigation of this novel hypothesis in the proposed study could substantially increase our understanding of modifiable risk factors for prostate cancer, especially for aggressive disease, and also specifically identify risk factors that contribute to disparities. The results of this study are highly translational (potentially by alterng melatonin levels and sleep patterns), and could illuminate opportunities for primary and secondary prevention. Moreover, the utilization of a large established cohort with pre-existing genetic data makes this study highly efficient and cost-effective.